MON-639 Melanocortin 4 Receptor Contributes to Glucose Homeostasis by Regulating Kidney Glucose Reabsorption via the Glucose Transporter GLUT2

Melanocortin 4 receptor (MC4R) is essential for normal body weight and food intake. Deficiency of MC4R causes obesity in humans and mice. While the function of MC4R is well established in appetite regulation, its direct role in glucose homeostasis is unclear. Humans and mice with MC4R deficiency exhibit hyperinsulinemia and insulin resistance; however, they remain protected from fasting hyperglycemia/diabetes. To determine the role of MC4R in glucose homeostasis, we performed oral glucose and intra-peritoneal insulin tolerance tests (OGTT / ITT) in male and female Mc4r knockout (KO) and wild type (WT) mice. Remarkably, Mc4r KO mice exhibited improved glucose tolerance compared to WT mice (Area under the curve for OGTT, male: 29,125±2,028 vs. 38,493±1,161 mg/dL.min; female: 36,322±1,100 vs. 49,539±1,911 mg/dL.min, p<0.0001). The improvement in glucose tolerance was despite insulin resistance in Mc4r KO mice (Plasma insulin, male: 9.9±1.7 vs. 0.7±0.1 ng/mL, female: 6.2±2.0 vs. 1.1±0.3 ng/mL, p<0.05; Area under the curve for ITT, male: 13,174±1,073 vs. 8,132±255 mg/dL.min; female: 13,927±1,253 vs. 7,506±267 mg/dL.min, p<0.01). Based on our previous findings from POMC deficient mice, we hypothesized that the improved glucose tolerance in the Mc4r KO mice is due to their elevated glycosuria (excretion of glucose in urine). To test this hypothesis, we challenged Mc4r KO and WT mice with oral glucose (250 mg) and collected their 24h urine to evaluate glycosuria. Indeed, the KO mice demonstrated elevated glycosuria compared to their WT littermates (Urine glucose, male: 284±48 vs. 0.4±0.03 mg/24h, female: 63.4±14 vs. 1±0.6 mg/24h, p<0.002). To assess molecular mechanisms underlying elevated glycosuria in Mc4r KO mice, we measured the gene expression and levels of the kidney glucose transporters GLUT1, GLUT2, SGLT1 and SGLT2. Glut2 mRNA was reduced by ~ 40% and the protein level was decreased by ~ 20% in Mc4r KO mice compared to their WT littermates. The other glucose transporters remained unchanged. Altogether, our study demonstrates that MC4R contributes to glucose homeostasis by regulating kidney glucose reabsorption via GLUT2. These findings may explain why MC4R deficient mice or humans remain protected from diabetes despite their longstanding obesity and insulin resistance.